Complement component 3 maintains a niche of IL-33+ adventitial fibroblasts during allergy 2668
Year: 2025
Type: article
Abstract: Description Mucosal complement component C3 is central to innate immunity. Our research identified the pulmonary mesenchyme, particularly adventitial fibroblasts (AFs), as an important source of C3. Notably, we found that C3+ AFs are enriched in IL-33, forming a distinct C3+IL-33+ population within the adventitia. These are present at steady state but significantly upregulate C3 and IL-33 production upon allergen exposure. We found that mesenchymal-derived IL-33 drives eosinophilia and activates group-2 innate lymphoid cells (ILC2s) in response to allergen. During allergic inflammation, C3 is crucial for maintaining IL-33 production in AFs, suggesting C3 acts upstream of IL-33 in AFs to promote type-2 immune responses. Fibroblast-specific deletion of C3 using C3flox mice significantly reduced allergen-induced eosinophilia and numbers of ILC2, highlighting mesenchymal C3 as a key regulator of innate type-2 immunity, likely through its control of stromal IL-33. Co-cultures of C3-sufficient or C3-deficient fibroblasts with ILC2s showed the importance of C3 in sustaining ILC2s. Additionally, examining the reverse aspect of this fibroblast-ILC2 crosstalk, we found that IL-13 signaling from ILC2s to fibroblasts is required to drive both C3 and IL-33 expression. Our data suggest that mesenchymal C3 sustains a niche of IL-33+ AFs that support ILC2s. In turn, innate IL-13 signaling reinforces this subset of AFs, forming a novel pathogenic circuit that amplifies type-2 inflammation. Funding Sources Supported by the Johns Hopkins Catalyst Award Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)
Source: The Journal of Immunology
Authors: Aishwarya Magesh, Aishwarya Atakkatan, Hwan Mee Yong, Elizabeth Murray, Naina Gour, Stephane Lajoie
Institution: Johns Hopkins University
Language: English
Topic: IL-33, ST2, and ILC Pathways
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416449829
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